Distinct Roles for Neutrophils and Dendritic Cells in Inflammation and Autoimmunity in motheaten Mice

Department of Laboratory Medicine and the Program in Immunology, University of California, San Francisco, San Francisco, CA 94143, USA.
Immunity (Impact Factor: 21.56). 03/2013; 38(3):489-501. DOI: 10.1016/j.immuni.2013.02.018
Source: PubMed


The motheaten mouse has long served as a paradigm for complex autoimmune and inflammatory disease. Null mutations in Ptpn6, which encodes the nonreceptor protein-tyrosine phosphatase Shp1, cause the motheaten phenotype. However, Shp1 regulates multiple signaling pathways in different hematopoietic cell types, so the cellular and molecular mechanism of autoimmunity and inflammation in the motheaten mouse has remained unclear. By using floxed Ptpn6 mice, we dissected the contribution of innate immune cells to the motheaten phenotype. Ptpn6 deletion in neutrophils resulted in cutaneous inflammation, but not autoimmunity, providing an animal model of human neutrophilic dermatoses. By contrast, dendritic cell deletion caused severe autoimmunity, without inflammation. Genetic and biochemical analysis showed that inflammation was caused by enhanced neutrophil integrin signaling through Src-family and Syk kinases, whereas autoimmunity resulted from exaggerated MyD88-dependent signaling in dendritic cells. Our data demonstrate that disruption of distinct Shp1-regulated pathways in different cell types combine to cause motheaten disease.

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    • "Analysis of serum cytokines demonstrated an elevation of proinflammatory cytokines such as MCP-1, IL-13, MIP-1α, IL-6, IP-10, MIG, and TCA in mice receiving TEL-Syk expressing fetal liver hematopoietic cells. Though we found no direct evidence of inflammatory induced tissue damage (such as pneumonitis or glomerulonephritis as is seen in other mouse models of inflammatory disease [25]), in combination with the anemia and thrombocytopenia, the proinflammatory nature of the MDS in the TEL-Syk chimeras may contribute to their poor survival. Elevated circulating levels of proinflammatory cytokines have been observed in a number of MPNs in humans. "
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    PLoS ONE 10/2013; 8(10):e77542. DOI:10.1371/journal.pone.0077542 · 3.23 Impact Factor
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